HIV inhibiting pyrazinone derivatives

ABSTRACT

This invention concerns a compound of formula 
                         
a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein R 1  is hydrogen, hydroxy, cyano, amino, mono-or di(C 1-4 alkyl)amino, formyl, carboxyl, C 1-6 alkyl, hydroxyC 1-6 alkyl, polyhaloC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, C 1-6 alkylcarbonyl, aminocarbonyl, —S(═O) m —NH 2 , mono-or di(C 1-4 alkyl)aminocarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkylcarbonyloxy, aryl, arylC 1-6 alkyl or aryloxy; R 2  is hydrogen; halo; mercapto; formyl; cyano; carboxy; azido; hydroxy; oxiranyl; amino; mono- or di(C 1-4 alkyl)amino; formylamino; R 5 R 6 N—C(═O)—; R 7 —N═C(R 8 )—; C 1-6 alkyl-S(═O)m; aryl-S(═O) m ; optionally substituted C 2-6 alkenyl; optionally substituted C 2-6 alkynyl; C 1-6 alkyloxy; hydroxyC 1-6 alkyloxy; aminoC 1-6 alkyloxy; mono- or di(C 1-4 alkyl)amino-C 1-6 alkyloxy; C 1-6 alkylcarbonyl; arylcarbonyl; Het 1 carbonyl; C 1-6 alkyloxycarbonyl; C 1-6 alkylcarbonyloxy; aryl; aryloxy; arylC 1-6 alkyloxy; arylthio; arylC 1-6 alkylthio; mono- or di(aryl)amino; Het 1 ; Het 1 oxy; Het 1 thio; Het 1 C 1-6 alkyloxy; Het 1 C 1-6 alkylthio; mono- or di(Het 1 )amino; C 3-7 cycloalkyl; C 3-7 cycloalkyloxy; C 3-7 cycloalkylthio; C 1-6 alkylthio; hydroxyC 1-6 alkylthio; aminoC 1-6 alkylthio; mono- or di(C 1-4 alkyl)aminoC 1-6 alkylthio; optionally substituted C 1-6 alkyl; R 3  or R 4  each independently represent optionally be substituted phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; —X— is a bivalent radical selected from —NR 14 —, —NH—NH—, —N═N—, —O—, —C 1-6 alkanediyl-, —C(═O)—, —CHOH—, —S—, —S(═O) m —; aryl is optionally substituted phenyl; Het 1 , Het 2  or Het 3  represent an optionally substituted monocyclic or bicyclic heterocycle; their use as a medicine, their processes for preparation and pharmaceutical compositions comprising them.

CROSS REFERENCE TO RELATED APPLICATIONS

This Application is a 35 U.S.C.

371 national phase application of PCT/EP02/02806, with an international filing date of Mar. 13, 2002, which claims priority to application EP 01200971.8, filed on Mar. 15, 2001, all of which are incorporated herein by reference in their entirety.

The present invention concerns pyrazinone derivatives having Human Immunodeficiency Virus (HIV) replication inhibiting properties. It also relates to their use as a medicine, their processes for preparation and pharmaceutical compositions comprising them.

GB 2,266,716 discloses pyrazine derivatives having HIV reverse transcriptase inhibiting activity.

WO 98/11075 describes pyrazinone derivatives as CRF (Corticotropin Releasing Factor) antagonists.

The present compounds differ from the prior art compounds by their structure or their activity, in particular their improved HIV replication inhibiting properties.

The present invention relates to novel compounds having the formula

the N-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms thereof, wherein

-   R¹ is hydrogen, hydroxy, cyano, amino, mono- or di(C₁₋₄alkyl)amino,     formyl, carboxyl, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, polyhaloC₁₋₆alkyl,     C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl, C₁₋₆alkyloxy,     C₁₋₆alkylcarbonyl, aminocarbonyl, —S(═O)_(m)—NH₂, mono- or     di(C₁₋₄alkyl)aminocarbonyl, C₁₋₆alkyloxycarbonyl,     C₁₋₆alkylcarbonyloxy, aryl, arylC₁₋₆alkyl or aryloxy; -   R² is hydrogen; halo; mercapto; formyl; cyano; carboxyl; azido;     hydroxy; oxiranyl; amino; mono- or di(C₁₋₄alkyl)amino; formylamino;     R⁵R⁶N—C(═O)—; R⁷—N═C(R⁸)—; C₁₋₆alkyl-S(═O)_(m); aryl-S(═O)_(m);     C₂₋₆alkenyl optionally substituted with one or two substituents each     independently selected from halo, hydroxy, cyano, formyl,     C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,     C₁₋₆alkylcarbonyloxy, N-hydroxy-imino, aryl or Het¹; C₂₋₆alkynyl     optionally substituted with one or two substituents each     independently selected from halo, hydroxy, cyano, formyl,     C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,     C₁₋₆alkylcarbonyloxy, N-hydroxy-imino, aryl or Het¹; C₁₋₆alkyloxy;     hydroxyC₁₋₆alkyloxy; aminoC₁₋₆alkyloxy; mono- or     di(C₁₋₄alkyl)amino-C₁₋₆alkyloxy; C₁₋₆alkylcarbonyl; arylcarbonyl;     Het¹carbonyl; C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyloxy; aryl;     aryloxy; arylC₁₋₆alkyloxy; arylthio; arylC₁₋₆alkylthio; mono- or     di(aryl)amino; Het¹; Het¹oxy; Het¹thio; Het¹C₁₋₆alkyloxy;     Het¹C₁₋₆alkylthio; mono- or di(Het¹)amino; C₃₋₇cycloalkyl;     C₃₋₇cycloalkyloxy; C₃₋₇cycloalkylthio; C₁₋₆alkylthio;     hydroxyC₁₋₆alkylthio; aminoC₁₋₆alkylthio; mono- or     di(C₁₋₄alkyl)aminoC₁₋₆alkylthio; C₁₋₆alkyl optionally substituted     with one, two or three substituents each independently selected from     halo, hydroxy, cyano, C₁₋₆alkyloxy, C₁₋₆alkylthio,     hydroxy-C₁₋₆alkyloxy, C₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy,     C₁₋₆alkylcarbonyl, C₁₋₆alkylcarbonyloxy, aminocarbonyloxy, mono- or     di(C₁₋₄alkyl)aminocarbonyloxy, C₁₋₆alkyloxycarbonyl,     C₁₋₆alkyloxycarbonyl-C₁₋₆alkyloxy,     C₁₋₆alkyloxycarbonylC₁₋₆alkylthio, aryl, Het¹, aryloxy, arylthio,     arylC₁₋₆alkyloxy, arylC₁₋₆alkylthio, Het¹C₁₋₆alkyloxy,     Het¹C₁₋₆alkylthio, C₁₋₆alkyl-S(═O)_(m)-oxy, amino, mono- or     di(C₁₋₆alkyl)amino, formylamino, C₁₋₆alkyloxycarbonylamino,     C₁₋₆alkyloxyC₁₋₆alkylcarbonylamino; mono- or di(aryl)amino, mono- or     di(arylC₁₋₄alkyl)amino, (C₁₋₆alkyl)(arylC₁₋₄alkyl)amino, mono- or     di(C₁₋₄alkyloxyC₁₋₄alkyl)amino, mono- or     di(arylC₁₋₄alkyloxy-C₁₋₄alkyl)amino, mono- or     di(C₁₋₄alkylthioC₁₋₄alkyl)amino, mono- or     di(arylC₁₋₄alkylthioC₁₋₄alkyl)amino, mono- or     di(Het¹C₁₋₄alkyl)amino, mono- or di(C₁₋₄alkyl)aminoC₁₋₄alkyloxy,     mono- or di(C₁₋₄alkyl)aminoC₁₋₄alkylthio, R⁹—C(═O)—NH—,     R¹⁰—NH—C(═O)—NH—, R¹¹—S(═O)₂—NH—, or a radical of formula

-   -   with A₁ representing CH or N, and A₂ representing CH₂, NR¹² or         O, provided that when A₁ is CH then A₂ is other than CH₂, said         radical of formula (a-1), (a-2) or (a-3) optionally being         substituted with one or two substituents each independently         selected from hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy,         hydroxyC₁₋₄alkyl, C₁₋₆alkyloxycarbonyl,         C₁₋₆alkyloxycarbonyl-C₁₋₄alkyl, aminoC₁₋₆alkyl, carbonyl,         hydroxy, cyano, amide, mono- or di(C₁₋₄alkyl)aminocarbonyl,         mono- or di(C₁₋₄alkyl)aminoC₁₋₆alkyl, 4-hydroxy-phenyl,         4-cyano-phenyl;

-   R³ and R⁴ each independently represent phenyl, pyridyl, pyrimidinyl,     pyrazinyl or pyridazinyl, wherein each of said aromatic rings may     optionally be substituted with one, two, three, four or five     substituents each independently selected from hydroxy, halo,     C₁₋₆alkyl optionally substituted with cyano or —C(═O)R¹³,     C₃₋₇cycloalkyl, C₂₋₆alkenyl optionally substituted with one or more     halogen atoms or cyano, C₂₋₆alkynyl optionally substituted with one     or more halogen atoms or cyano, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,     carboxyl, cyano, aminocarbonyl, nitro, amino, mono- or     di(C₁₋₆alkyl)amino, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy,     polyhaloC₁₋₆alkylthio, —S(═O)_(p)R¹³, —NH—S(═O)_(p)R¹³, —C(═O)R¹³,     —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R¹³, —C(═NH)R¹³ or a radical of     formula

wherein each A independently is N, CH or CR¹³;

-   -   B is NH, O, S or NR¹³;     -   p is 1 or 2; and

-   —X— is a bivalent radical selected from —NR¹⁴—; —NH—NH—; —N═N—; —O—;     —C₁₋₆alkanediyl- which may optionally be substituted with halo,     C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy, mono- or     di(C₁₋₆alkyl)amino, mono- or di(C₁₋₆alkyl)aminocarbonyl; —C(═O)—;     —CHOH—; —S—; —S(═O)_(m)-;

-   each m independently is 1 or 2;

-   R⁵ and R⁶ each independently represent hydrogen or C₁₋₄alkyl     optionally substituted with cyano, C₁₋₄alkyloxy, C₁₋₄alkylthio,     amino, mono- or di(C₁₋₄alkyl)amino or a radical of formula

-    with A₃ and A₄ each independently representing CH₂, NR¹² or O; -   R⁷ is hydrogen, hydroxy, C₁₋₄alkyloxy, carboxyC₁₋₄alkyloxy,     C₁₋₄alkyloxycarbonylC₁₋₄alkyloxy, C₂₋₄alkenyloxy, C₂₋₄alkynyloxy or     arylC₁₋₄alkyloxy; -   R⁸ is hydrogen, carboxyl or C₁₋₄alkyl; -   R⁹ is hydrogen; C₁₋₄alkyl optionally substituted with cyano,     C₁₋₄alkyloxy, C₁₋₄alkyl-S(═O)_(m)—, aryl or Het²; C₁₋₄alkyloxy;     C₂₋₄alkenyl; arylC₂₋₄alkenyl; Het²C₂₋₄alkenyl; C₂₋₄alkynyl;     Het²C₂₋₄alkynyl; arylC₂₋₄alkynyl; C₃₋₇cycloalkyl; aryl; naphthyl; or     Het²; -   R¹⁰ is C₁₋₄alkyl, arylC₁₋₄alkyl, aryl, arylcarbonyl,     C₁₋₄alkylcarbonyl, C₁₋₄alkyloxycarbonyl,     C₁₋₄alkyloxycarbonylC₁₋₄alkyl; -   R¹¹ is C₁₋₄alkyl optionally substituted with aryl or Het³,     polyhaloC₁₋₄alkyl, or C₂₋₄alkenyl optionally substituted with aryl     or Het³; -   R¹² is hydrogen, C₁₋₄alkyl or C₁₋₄alkylcarbonyl; -   R¹³ is C₁₋₆alkyl, amino, mono- or di(C₁₋₆alkyl)amino or     polyhaloC₁₋₆alkyl; -   R¹⁴ is hydrogen; aryl; formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl;     C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with formyl,     C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy;     C₁₋₆alkyloxyC₁₋₄alkylcarbonyl substituted with C₁₋₆alkyloxycarbonyl; -   aryl is phenyl optionally substituted with one, two, three, four or     five substituents each independently selected from hydroxy, halo,     C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro,     polyhaloC₁₋₆alkyl and polyhaloC₁₋₆alkyloxy; -   Het¹ represents a monocyclic or bicyclic heterocycle selected from     pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl,     pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolidinyl,     tetrahydrofuranyl, tetrahydrothienyl, imidazolidinyl, oxazolidinyl,     thiazolidinyl, piperidinyl, hexahydropyrimidinyl, piperazinyl,     hexahydropyridazinyl, benzopyrrolyl, benzofuranyl, benzothienyl,     benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl,     2-oxo-1,2-dihydroquinolinyl, each of said monocyclic or bicyclic     heterocycle may optionally be substituted with one, two or three     substituents each independently selected from halo, hydroxy,     C₁₋₄alkyl, C₁₋₄alkyloxy, C₁₋₄alkylcarbonyl or polyhaloC₁₋₄alkyl; -   Het² represents a monocyclic or bicyclic heterocycle selected from     pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl,     pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl,     pyrazinyl, pyridazinyl, benzopyrrolyl, benzofuranyl, benzothienyl,     benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl,     quinolinyl, 2-oxo-1,2-dihydro-quinolinyl, quinolinonyl,     pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, imidazolidinyl,     oxazolidinyl, thiazolidinyl, piperidinyl, hexahydropyrimidinyl,     piperazinyl, hexahydropyridazinyl or a radical of formula

-    with A₅ or A₆ each independently being selected from CH₂ or O; each     of said monocyclic or bicyclic heterocycle may optionally be     substituted with one, two or three substituents each independently     selected from halo, hydroxy,C₁₋₄alkyl, C₁₋₄alkyloxy,     C₁₋₄alkylcarbonyl, polyhaloC₁₋₄alkyl or aryl; -   Het³ represents a monocyclic heterocycle selected from pyrrolyl,     furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyridyl,     pyrimidinyl, pyrazinyl, pyridazinyl, each of said heterocycle may     optionally be substituted with one, two or three substituents each     independently selected from halo, hydroxy, C₁₋₄alkyl, C₁₋₄alkyloxy,     C₁₋₄alkylcarbonyl or polyhaloC₁₋₄alkyl.

As used hereinbefore or hereinafter C₁₋₂alkyl as a group or part of a group defines methyl or ethyl; C₁₋₃alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 3 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl; C₁₋₄alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as the group defined for C₁₋₃alkyl and butyl, 1-methyl-propyl and the like; C₁₋₆alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as the group defined for C₁₋₄alkyl and pentyl, hexyl, 2-methylbutyl and the like; C₁₋₆alkanediyl defines straight or branched chain saturated bivalent hydrocarbon radicals having from 1 to 6 carbon atoms such as methylene, 1,2-ethanediyl or 1,2-ethylidene, 1,3-propanediyl or 1,3-propylidene, 1,4-butanediyl or 1,4-butylidene, 1,5-pentylidene, 1,6-hexylidene and the like; C₂₋₄alkenyl defines straight and branched chain hydrocarbon radicals having from 2 to 4 carbon atoms containing a double bond such as ethenyl, propenyl, butenyl and the like; C₂₋₆alkenyl defines straight and branched chain hydrocarbon radicals having from 2 to 6 carbon atoms containing a double bond such as the group defined for C₂₋₄alkenyl and pentenyl, hexenyl and the like; C₂₋₄alkynyl defines straight and branched chain hydrocarbon radicals having from 2 to 4 carbon atoms containing a triple bond such as ethynyl, propynyl, butynyl and the like; C₂₋₆alkynyl defines straight and branched chain hydrocarbon radicals having from 2 to 6 carbon atoms containing a triple bond such as the group defined for C₂₋₄alkynyl and pentynyl, hexynyl and the like; C₃₋₇cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

As used herein before, the term (═O) forms a carbonyl moiety when attached to a carbon atom, a sulfoxide moiety when attached to a sulfur atom and a sulfonyl moiety when two of said terms are attached to a sulfur atom.

The term halo is generic to fluoro, chloro, bromo and iodo. As used in the foregoing and hereinafter, polyhalomethyl as a group or part of a group is defined as mono- or polyhalosubstituted methyl, in particular methyl with one or more fluoro atoms, for example, difluoromethyl or trifluoromethyl; polyhaloC₁₋₆alkyl as a group or part of a group is defined as mono- or polyhalosubstituted C₁₋₆alkyl, for example, the groups defined in halomethyl, 1,1-difluoro-ethyl and the like. In case more than one halogen atoms are attached to an alkyl group within the definition of polyhalomethyl or polyhaloC₁₋₆alkyl, they may be the same or different.

Het¹, Het² and Het³ are meant to include all the possible isomeric forms of the heterocycles mentioned in the definition of Het¹, Het² and Het³. For instance, when Het¹, Het² or Het³ represent pyrrolyl, this also includes 2H-pyrrolyl

The Het¹, Het² or Het³ radical may be attached to the remainder of the molecule of formula (I) through any ring carbon or heteroatom as appropriate, if not otherwise specified. Thus, for example, when the heterocycle is imidazolyl, it may be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and the like.

When any variable (eg. aryl, R¹³ etc.) occurs more than one time in any constituent, each definition is independent.

Lines drawn into ring systems indicate that the bond may be attached to any of the suitable ring atoms.

For therapeutic use, salts of the compounds of formula (I) are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.

The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, for example, hydrohalic acids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base form.

The compounds of formula (I) containing acidic protons may be converted into their therapeutically active non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline, the benzathine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the salt form can be converted by treatment with acid into the free acid form.

The term addition salt also comprises the hydrates and solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.

The term “quaternary amine” as used hereinbefore defines the quaternary ammonium salts which the compounds of formula (I) are able to form by reaction between a basic nitrogen of a compound of formula (I) and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide. Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine has a positively charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins.

It will be appreciated that some of the compounds of formula (I) and their N-oxides, addition salts, quaternary amines and stereochemically isomeric forms may contain one or more centers of chirality and exist as stereochemically isomeric forms.

The term “stereochemically isomeric forms” as used hereinbefore defines all the possible stereoisomeric forms which the compounds of formula (I), and their N-oxides, addition salts, quaternary amines or physiologically functional derivatives may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure as well as each of the individual isomeric forms of formula (I) and their N-oxides, salts, solvates or quaternary amines substantially free, i.e. associated with less than 10%, preferably less than 5%, in particular less than 2% and most preferably less than 1% of the other isomers. In particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration. Compounds encompassing double bonds can have an E or Z-stereochemistry at said double bond. Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of this invention.

The N-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several tertiary nitrogen atoms are oxidized to the so-called N-oxide.

Some of the compounds of formula (I) may also exist in their tautomeric form. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.

Whenever used hereinafter, the term “compounds of formula (I)” is meant to also include their N-oxide forms, their salts, their quaternary amines and their stereochemically isomeric forms. Of special interest are those compounds of formula (I) which are stereochemically pure.

An interesting group of compounds of formula (I) are those compounds wherein

-   R¹ is hydrogen, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, polyhaloC₁₋₆alkyl,     C₂₋₆alkenyl, C₂₋₆alkynyl, aryl, arylC₁₋₆alkyl or aryloxy; -   R² is hydrogen; halo; C₁₋₆alkyloxy; hydroxyC₁₋₆alkyloxy;     aminoC₁₋₆alkyloxy; mono- or di(C₁₋₄alkyl)amino-C₁₋₆alkyloxy; aryl;     aryloxy; arylC₁₋₆alkyloxy; arylthio; arylC₁₋₆alkylthio; Het¹;     Het¹oxy; Het¹thio; Het¹C₁₋₆alkyloxy; Het¹C₁₋₆alkylthio; C₁₋₆alkyl     optionally substituted with one, two or three substituents each     independently selected from halo, hydroxy, cyano, C₁₋₆alkyloxy,     C₁₋₆alkylthio, aryl, Het¹, aryloxy, arylthio, arylC₁₋₆alkyloxy,     arylC₁₋₆alkylthio, Het¹C₁₋₆alkyloxy, Het¹C₁₋₆alkylthio, -   R³ and R⁴ each independently represent phenyl, pyridyl, pyrimidinyl,     pyrazinyl or pyridazinyl, wherein each of said aromatic rings may     optionally be substituted with one, two, three, four or five     substituents each independently selected from hydroxy, halo,     C₁₋₆alkyl, cyano, aminocarbonyl, polyhaloC₁₋₆alkyl,     polyhaloC₁₋₆alkyloxy, polyhaloC₁₋₆alkylthio; -   —X— is a bivalent radical selected from —NR¹⁴—; —NH—NH—; —N═N—; —O—;     —C₁₋₆alkanediyl-; —C(═O)—; —CHOH—; —S—; —S(═O)_(m)-; -   each m independently is 1 or 2; -   R¹⁴ is hydrogen; aryl; formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl;     C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with formyl,     C₁₋₄alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy;     C₁₋₆alkyloxyC₁₋₆alkylcarbonyl substituted with C₁₋₆alkyloxycarbonyl; -   aryl is phenyl optionally substituted with one, two, three, four or     five substituents each independently selected from hydroxy, halo,     C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro,     polyhaloC₁₋₆alkyl and polyhaloC₁₋₆alkyloxy;, -   Het¹ represents a monocyclic or bicyclic heterocycle selected from     pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl,     pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolidinyl,     tetrahydrofuranyl, tetrahydrothienyl, imidazolidinyl, oxazolidinyl,     thiazolidinyl, piperidinyl, hexahydropyrimidinyl, piperazinyl,     hexahydropyridazinyl, benzopyrrolyl, benzofuranyl, benzothienyl,     benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl,     2-oxo-1,2-dihydro-quinolinyl, each of said monocyclic or bicyclic     heterocycle may optionally be substituted with one, two or three     substituents each independently selected from halo, hydroxy,     C₁₋₄alkyl, C₁₋₄alkyloxy, C₁₋₄alkylcarbonyl or polyhaloC₁₋₄alkyl;

Particular groups of compounds of formula (I) are those groups wherein one or more, preferably all, of the following conditions are met:

-   i) R¹ is hydrogen, C₁₋₆ alkyl or arylC₁₋₆alkyl; or -   ii) R² is hydrogen, C₁₋₆alkyl or arylthio; or -   iii) R³ is optionally substituted phenyl; or -   iv) R⁴ is optionally substituted phenyl; or -   v) X is O, S or S(═O)_(m).

Further particular compounds of formula (I) are those compounds wherein R¹ is hydrogen or wherein R¹ is C₁₋₃alkyl or arylC₁₋₆alkyl, especially wherein R¹ is methyl.

Also particular compounds of formula (I) are those compounds wherein R² is hydrogen or C₁₋₆alkyl, especially methyl.

Still further interesting compounds of formula (I) are those compounds wherein R³ or R⁴ is phenyl substituted with one, two or three substituents selected from cyano, aminocarbonyl, C₁₋₆alkyl, halo, polyhaloC₁₋₆alkyl.

Yet further interesting compounds of formula (I) are those compounds wherein R⁴ is phenyl substituted with cyano, aminocarbonyl, C₁₋₆alkyl, halo, polyhalomethyl, preferably cyano or aminocarbonyl. Preferred compounds of formula (I) are selected from:

-   4-[[3,4-dihydro-4-methyl-6-(2-methylphenoxy)-3-oxopyrazinyl]amino]-benzonitrile; -   4-[[6-(2,4-dimethylphenoxy)-3,4-dihydro-4-methyl-3-oxopyrazinyl]amino]-benzonitrile; -   4-[[3,4-dihydro-4-methyl-6-[(2-methylphenyl)thio]-3-oxopyrazinyl]amino]-benzonitrile; -   3-[(4-chlorophenyl)amino]-1,6-dimethyl-5-(2-methylphenoxy)-2(1H)-pyrazinone; -   5-(2,4-dimethylphenoxy)-1-methyl-3-(phenylamino)-2(1H)-pyrazinone; -   3-[(4-chlorophenyl)amino]-5-[(2,4-dimethylphenyl)thio]-1,6-dimethyl-2(1H)-pyrazinone; -   4-[[6-(2,4-dimethylphenoxy)-3,4-dihydro-3-oxo-4-(phenylmethyl)pyrazinyl]amino]-benzonitrile; -   4-[[6-(2,4-dimethylphenoxy)-3,4-dihydro-3-oxo-4-(phenylmethyl)pyrazinyl]amino]-benzonitrile; -   5-(2,4-dimethylphenoxy)-1-methyl-3-[[4-(trifluoromethyl)phenyl]amino]-2(1H)-pyrazinone; -   5-(2,4-dimethylphenoxy)-1-methyl-3-[[4-(trifluoromethyl)phenyl]amino]-2(1H)-pyrazinone; -   4-[[3,4-dihydro-4-methyl-3-oxo-6-[(2,4,6-trimethylphenyl)thio]pyrazinyl]amino]-benzonitrile; -   3-[(4-chlorophenyl)amino]-1-methyl-5-[(2,4,6-trimethylphenyl)thio]-2(1H)-pyrazinone; -   4-[[3,4-dihydro-4-methyl-3-oxo-6-[(2,4,6-trimethylphenyl)sulfonyl]pyrazinyl]amino]-benzonitrile; -   4-[[6-[(2,4-dimethylphenyl)sulfonyl]-3,4-dihydro-4,5-dimethyl-3-oxopyrazinyl]amino]-benzonitrile; -   4-[[3,4-dihydro-4,5-dimethyl-3-oxo-6-[(2,4,6-trimethylphenyl)sulfonyl]pyrazinyl]amino]-benzonitrile; -   4-[[3,4-dihydro-4,5-dimethyl-3-oxo-6-[(2,4,6-trimethylphenyl)sulfonyl]pyrazinyl]amino]-benzonitrile; -   4-[[3,4-dihydro-4,5-dimethyl-6-(2-methylphenoxy)-3-oxopyrazinyl]amino]-benzonitrile; -   4-[[6-(2,4-dimethylphenoxy)-3,4-dihydro-4,5-dimethyl-3-oxopyrazinyl]amino]-benzonitrile; -   4-[[6-[(2,4-dimethylphenyl)thio]-3,4-dihydro-4-methyl-3-oxopyrazinyl]amino]-benzonitrile; -   3-[(4-chlorophenyl)amino]-5-(2,4-dimethylphenoxy)-1-methyl-2(1H)-pyrazinone; -   3-[(4-chlorophenyl)amino]-5-(2,4-dimethylphenoxy)-1,6-dimethyl-2(1H)-pyrazinone; -   4-[[3,4-dihydro-4,5-dimethyl-6-[(2-methylphenyl)thio]-3-oxopyrazinyl]amino]-benzonitrile; -   3-[(4-chlorophenyl)amino]-5-(2,4-dimethylphenylthio)-1,6-dimethyl-2(1H)-pyrazinone; -   4-[[6-[(4-cyanophenyl)amino]-4,5-dihydro-3,4-dimethyl-5-oxopyrazinyl]oxy]-3,5-dimethyl-benzonitrile; -   4-[4,5-dimethyl-3-oxo-6-(2,4,6-trimethyl-phenylsulfanyl)-3,4-dihydro-pyrazin-2-ylamino]-benzonitrile; -   4-[[6-[(2-methylphenyl)thio]-5-methyl-3,4-dihydro-3-oxo-4-(phenylmethyl)pyrazinyl]amino]-benzonitrile; -   4-[[3,4-dihydro-5-methyl-6-[(2-methylphenyl)thio]-3-oxopyrazinyl]amino]-benzonitrile; -   4-[[6-(2,4-dimethylphenoxy)-5-methyl-3,4-dihydro-3-oxo-4-(phenylmethyl)pyrazinyl]amino]-benzonitrile; -   5-(2,4,6-trimethylphenoxy)-5-methyl-1-methyl-3-[[4-(trifluoromethyl)phenyl]amino]-2(1H)-pyrazinone;     their N-oxides, pharmaceutically acceptable addition salts,     quaternary amines and stereochemically isomeric forms thereof.

Also preferred compounds of formula (I) are those compounds selected from

-   4-[[3,4-dihydro-4-methyl-6-(2-methylphenoxy)-3-oxopyrazinyl]amino]-benzonitrile; -   4-[[6-(2,4-dimethylphenoxy)-3,4-dihydro-4-methyl-3-oxopyrazinyl]amino]-benzonitrile; -   4-[[3,4-dihydro-4-methyl-6-[(2-methylphenyl)thio]-3-oxopyrazinyl]amino]-benzonitrile; -   3-[(4-chlorophenyl)amino]-1,6-dimethyl-5-(2-methylphenoxy)-2(1H)-pyrazinone; -   5-(2,4-dimethylphenoxy)-1-methyl-3-(phenylamino)-2(1H)-pyrazinone; -   3-[(4-chlorophenyl)amino]-5-[(2,4-dimethylphenyl)thio]-1,6-dimethyl-2(1H)-pyrazinone; -   4-[[6-(2,4-dimethylphenoxy)-3,4-dihydro-3-oxo-4-(phenylmethyl)pyrazinyl]amino]-benzonitrile, -   4-[[6-(2,4-dimethylphenoxy)-3,4-dihydro-3-oxo-4-(phenylmethyl)pyrazinyl]amino]-benzonitrile; -   5-(2,4-dimethylphenoxy)-1-methyl-3-[[4-(trifluoromethyl)phenyl]amino]-2(1H)-pyrazinone, -   5-(2,4-dimethylphenoxy)-1-methyl-3-[[4-(trifluoromethyl)phenyl]amino]-2(1H)-pyrazinone, -   4-[[3,4-dihydro-4-methyl-3-oxo-6-[(2,4,6-trimethylphenyl)thio]pyrazinyl]amino]-benzonitrile; -   3-[(4-chlorophenyl)amino]-1-methyl-5-[(2,4,6-trimethylphenyl)thio]-2(1H)-pyrazinone, -   4-[[3,4-dihydro-4-methyl-3-oxo-6-[(2,4,6-trimethylphenyl)sulfonyl]pyrazinyl]amino]-benzonitrile; -   4-[[6-[(2,4-dimethylphenyl)sulfonyl]-3,4-dihydro-4,5-dimethyl-3-oxopyrazinyl]amino]-benzonitrile, -   4-[[3,4-dihydro-4,5-dimethyl-3-oxo-6-[(2,4,6-trimethylphenyl)sulfonyl]pyrazinyl]amino]-benzonitrile; -   4-[[3,4-dihydro-4,5-dimethyl-3-oxo-6-[(2,4,6-trimethylphenyl)sulfonyl]pyrazinyl]amino]-benzonitrile; -   4-[[3,4-dihydro-4,5-dimethyl-6-(2-methylphenoxy)-3-oxopyrazinyl]amino]-benzonitrile, -   4-[[6-(2,4-dimethylphenoxy)-3,4-dihydro-4,5-dimethyl-3-oxopyrazinyl]amino]-benzonitrile -   4-[[6-[(2,4-dimethylphenyl)thio]-3,4-dihydro-4-methyl-3-oxopyrazinyl]amino]-benzonitrile; -   3-[(4-chlorophenyl)amino]-5-(2,4-dimethylphenoxy)-1-methyl-2(1H)-pyrazinone; -   3-[(4-chlorophenyl)amino]-5-(2,4-dimethylphenoxy)-1,6-dimethyl-2(1H)-pyrazinone; -   4-[[3,4-dihydro-4,5-dimethyl-6[(2-methylphenyl)thio]-3-oxopyrazinyl]amino]-benzonitrile; -   3-[(4-chlorophenyl)amino]-5-(2,4-dimethylphenylthio)-1,6-dimethyl-2(1H)-pyrazinone; -   4-[[6-[(4-cyanophenyl)amino]-4,5-dihydro-3,4-dimethyl-5-oxopyrazinyl]oxy]-3,5-dimethyl-benzonitrile; -   4-[4,5-dimethyl-3-oxo-6-(2,4,6-trimethyl-phenylsulfanyl)-3,4-dihydro-pyrazin-2-ylamino]-benzonitrile;     a N-oxide, a pharmaceutically acceptable addition salt, a quaternary     amine and a stereochemically isomeric form thereof.

Especially preferred compounds of formula (I) are selected from

-   4-[[3,4-dihydro-4,5-dimethyl-6-(2-methylphenoxy)-3-oxopyrazinyl]amino]-benzonitrile; -   4-[[6-(2,4-dimethylphenoxy)-3,4-dihydro-4,5-dimethyl-3-oxopyrazinyl]amino]-benzonitrile; -   4-[[6-[(2,4-dimethylphenyl)thio]-3,4-dihydro-4-methyl-3-oxopyrazinyl]amino]-benzonitrile; -   4-[[6-[(4-cyanophenyl)amino]-4,5-dihydro-3,4-dimethyl-5-oxopyrazinyl]oxy]-3,5-dimethyl-benzonitrile;     their N-oxides, pharmaceutically acceptable addition salts,     quaternary amines and stereochemically isomeric forms thereof.

In general, the compounds of formula (I) may be prepared by reacting an intermediate of formula (II), wherein W₁ represents a suitable leaving group, such as a halogen atom, e.g. chloro, bromo and the like, with an intermediate of formula (III) in the presence of a suitable catalyst, such as for example CuCl, palladium acetate, palladium tetrakis(triphenylphosphine), a suitable base, such as for example Cs₂CO₃, and a suitable solvent, such as for example toluene or 1-methyl-2-pyrrolidinone, optionally in the presence of ethyl acetate only or combined with 2,4,6-(tri-tert-butyl)-phenol or optionally in the presence of naphtoic acid. Said reaction may preferably be performed at elevated temperatures and may optionally be performed under N₂ atmosphere.

Compounds of formula (I) may be converted into each other following art-known functional group transformation reactions, comprising those described hereinafter.

The compounds of formula (I) may be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tert butyl hydro-peroxide. Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.

Compounds of formula (I), wherein X represents S, said compounds being represented by formula (I-a), may be converted into a compound of formula (I), wherein X represents S(═O)_(m), said compound being represented by formula (I-b), in the presence of a suitable oxidizing agent, such as a peroxide, for example, chloroperbenzoic acid, in the presence of a suitable solvent, such as for example dichloromethane.

Compounds of formula (I), wherein R¹ is optionally substituted C₁₋₆alkyl, said R¹ being represented by R^(1a) and said compounds being represented by formula (I-c), can be dealkylated to a compound of formula (I), wherein R¹ is hydrogen, said compound being represented by formula (I-d). Therefor, a compound of formula (I-c) is first dealkylated with a suitable agent, such as for example PO(W₂)₃, wherein W₂ represents a suitable leaving group, such as a halogen atom, for example chloro, resulting in the formation of an intermediate of formula (IV), with W₂ as defined above. Said intermediate of formula (IV) may subsequently be reacted with a suitable alcoholate, such as for example C₁₋₂alkylO⁻Na⁺, e.g. methanolate or ethanolate, in the presence of a suitable solvent, such as an alcohol, for example methanol, ethanol and the like, resulting in the formation of an intermediate of formula (V), which can be dealkylated into a compound of formula (I-d) by reaction with a suitable agent, such as for example BBr₃.

Compounds of formula (I-d) may also be prepared by deprotecting a compound of formula (I-c) wherein R^(1a) is arylC₁₋₆alkyl, said compound being represented by formula (I-c-1), in the presence of a suitable agent, such as AlCl₃, and in the presence of a suitable solvent, such as for example o-dichlorobenzene. The reaction may be performed under N₂ atmosphere and at elevated temperatures.

In the following paragraphs, there are described several methods of preparing the intermediates in the foregoing preparations. A number of intermediates and starting materials are commercially available or are known compounds which may be prepared according to conventional reaction procedures generally known in the art.

Intermediates of formula (II) can be prepared by reacting an intermediate of formula (VI) with an intermediate of formula (VII) in the presence of a suitable acid, such as for example a sulfonic acid, e.g. camphor sulfonic acid, trifluoromethane sulfonic acid and the like, and a suitable solvent, such as an alcohol, for example isopropanol and the like. Said reaction is preferably performed at elevated temperatures.

Intermediates of formula (VI) can be prepared by reacting an intermediate of formula (VIII), wherein W₁ is as defined above, with an intermediate of formula (IX), wherein W₁ is as defined above, in the presence of a suitable solvent, such as for example N,N-dimethylformamide, chlorobenzene, dichloromethane, chloroform, optionally in the presence of a suitable salt, such as for example tetraethylammonium bromide.

Intermediates of formula (VI), wherein R¹ is hydrogen, said intermediates being represented by formula (VI-a), can also be prepared by reacting an intermediate of formula (X) with a suitable halogenating agent, such as for example N-bromosuccinimide, in the presence of a suitable base, such as for example disodium carbonate, and a suitable solvent, such as for example N,N-dimethylformamide.

The compounds of formula (I) as prepared in the hereinabove described processes may be synthesized as a mixture of stereoisomeric forms, in particular in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

The compounds of formula (I) show antiretroviral properties, in particular against Human Immunodeficiency Virus (HIV), which is the aetiological agent of Acquired Immune Deficiency Syndrome (AIDS) in humans. The HIV virus preferentially infects human T-4 cells and destroys them or changes their normal function, particularly the coordination of the immune system. As a result, an infected patient has an everdecreasing number of T-4 cells, which moreover behave abnormally. Hence, the immunological defense system is unable to combat infections and neoplasms and the HIV infected subject usually dies by opportunistic infections such as pneumonia, or by cancers. Other conditions associated with HIV infection include thrombocytopaenia, Kaposi's sarcoma and infection of the central nervous system characterized by progressive demyelination, resulting in dementia and symptoms such as, progressive dysarthria, ataxia and disorientation. HIV infection further has also been associated with peripheral neuropathy, progressive generalized lymphadenopathy (PGL) and AIDS-related complex (ARC).

The present compounds also show activity against multi drug resistant HIV strains, in particular multi drug resistant HIV-1 strains, more in particular the present compounds show activity against HIV strains, especially HIV-1 strains, that have acquired resistance to art-known non-nucleoside reverse transcriptase inhibitors. Art-known non-nucleoside reverse transcriptase inhibitors are those non-nucleoside reverse transcriptase inhibitors other than the present compounds. They also have little or no binding affinity to human α-1 acid glycoprotein.

Due to their antiretroviral properties, particularly their anti-HIV properties, especially their anti-HIV-1-activity, the compounds of formula (I), their N-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms thereof, are useful in the treatment of individuals infected by HIV and for the prophylaxis of these infections. In general, the compounds of the present invention may be useful in the treatment of warm-blooded animals infected with viruses whose existence is mediated by, or depends upon, the enzyme reverse transcriptase. Conditions which may be prevented or treated with the compounds of the present invention, especially conditions associated with HIV and other pathogenic retroviruses, include AIDS, AIDS-related complex (ARC), progressive generalized lymphadenopathy (PGL), as well as chronic CNS diseases caused by retroviruses, such as, for example HIV mediated dementia and multiple sclerosis.

The compounds of the present invention or any subgroup thereof may therefore be used as medicines against above-mentioned conditions. Said use as a medicine or method of treatment comprises the systemic administration to HIV-infected subjects of an amount effective to combat the conditions associated with HIV and other pathogenic retroviruses, especially HIV-1. In particular, the compounds of formula (I) may be used in the manufacture of a medicament for the treatment or the prevention of HIV infections.

In view of the utility of the compounds of formula (I), there is provided a method of treating warm-blooded animals, including humans, suffering from or a method of preventing warm-blooded animals, including humans, to suffer from viral infections, especially HIV infections. Said method comprises the administration, preferably oral administration, of an effective amount of a compound of formula (I), a N-oxide form, a pharmaceutically acceptable addition salt, a quaternary amine or a possible stereoisomeric form thereof, to warm-blooded animals, including humans.

The present invention also provides compositions for treating viral infections comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.

The compounds of the present invention or any subgroup thereof may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols (e.g. polyethylene glycols), oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.

The compounds of the present invention may also be administered via inhalation or insufflation by means of methods and formulations employed in the art for administration via this way. Thus, in general the compounds of the present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder. Any system developed for the delivery of solutions, suspensions or dry powders via oral or nasal inhalation or insufflation are suitable for the administration of the present compounds.

To aid solubility of the compounds of formula (I), suitable ingredients, e.g. cyclodextrins, may be included in the compositions. Appropriate cyclodextrins are α-, β-, γ-cyclodextrins or ethers and mixed ethers thereof wherein one or more of the hydroxy groups of the anhydroglucose units of the cyclodextrin are substituted with C₁₋₆alkyl, particularly methyl, ethyl or isopropyl, e.g. randomly methylated β-CD; hydroxyC₁₋₆alkyl, particularly hydroxyethyl, hydroxy-propyl or hydroxybutyl; carboxyC₁₋₆alkyl, particularly carboxymethyl or carboxy-ethyl; C₁₋₆alkylcarbonyl, particularly acetyl. Especially noteworthy as complexants and/or solubilizers are β-CD, randomly methylated β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD, 2-hydroxyethyl-γ-CD, 2-hydroxypropyl-γ-CD and (2-carboxymethoxy)propyl-β-CD, and in particular 2-hydroxypropyl-β-CD (2-HP-β-CD)

The term mixed ether denotes cyclodextrin derivatives wherein at least two cyclodextrin hydroxy groups are etherified with different groups such as, for example, hydroxy-propyl and hydroxyethyl.

The average molar substitution (M.S.) is used as a measure of the average number of moles of alkoxy units per mole of anhydroglucose. The average substitution degree (D.S.) refers to the average number of substituted hydroxyls per anhydroglucose unit. The M.S. and D.S. value can be determined by various analytical techniques such as nuclear magnetic resonance (NMR), mass spectrometry (MS) and infrared spectroscopy (IR). Depending on the technique used, slightly different values may be obtained for one given cyclodextrin derivative. Preferably, as measured by mass spectrometry, the M.S. ranges from 0.125 to 10 and the D.S. ranges from 0.125 to 3.

Other suitable compositions for oral or rectal administration comprise particles consisting of a solid dispersion comprising a compound of formula (I) and one or more appropriate pharmaceutically acceptable water-soluble polymers.

The term “a solid dispersion” used hereinafter defines a system in a solid state (as opposed to a liquid or gaseous state) comprising at least two components, in casu the compound of formula (I) and the water-soluble polymer, wherein one component is dispersed more or less evenly throughout the other component or components ( in case additional pharmaceutically acceptable formulating agents, generally known in the art, are included, such as plasticizers, preservatives and the like). When said dispersion of the components is such that the system is chemically and physically uniform or homogenous throughout or consists of one phase as defined in thermo-dynamics, such a solid dispersion will be called “a solid solution”. Solid solutions are preferred physical systems because the components therein are usually readily bioavailable to the organisms to which they are administered. This advantage can probably be explained by the ease with which said solid solutions can form liquid solutions when contacted with a liquid medium such as the gastro-intestinal juices. The ease of dissolution may be attributed at least in part to the fact that the energy required for dissolution of the components from a solid solution is less than that required for the dissolution of components from a crystalline or microcrystalline solid phase.

The term “a solid dispersion” also comprises dispersions which are less homogenous throughout than solid solutions. Such dispersions are not chemically and physically uniform throughout or comprise more than one phase. For example, the term “a solid dispersion” also relates to a system having domains or small regions wherein amorphous, microcrystalline or crystalline compound of formula (I), or amorphous, microcrystalline or crystalline water-soluble polymer, or both, are dispersed more or less evenly in another phase comprising water-soluble polymer, or compound of formula (I), or a solid solution comprising compound of formula (I) and water-soluble polymer. Said domains are regions within the solid dispersion distinctively marked by some physical feature, small in size, and evenly and randomly distributed throughout the solid dispersion.

Various techniques exist for preparing solid dispersions including melt-extrusion, spray-drying and solution-evaporation.

The solution-evaporation process comprises the following steps:

-   a) dissolving the compound of formula (I) and the water-soluble     polymer in an appropriate solvent, optionally at elevated     temperatures; -   b) heating the solution resulting under point a), optionally under     vacuum, until the solvent is evaporated. The solution may also be     poured onto a large surface so as to form a thin film, and     evaporating the solvent therefrom.

In the spray-drying technique, the two components are also dissolved in an appropriate solvent and the resulting solution is then sprayed through the nozzle of a spray dryer followed by evaporating the solvent from the resulting droplets at elevated temperatures.

The preferred technique for preparing solid dispersions is the melt-extrusion process comprising the following steps:

-   -   a) mixing a compound of formula (I) and an appropriate         water-soluble polymer,     -   b) optionally blending additives with the thus obtained mixture,     -   c) heating and compounding the thus obtained blend until one         obtains a homogenous melt,     -   d) forcing the thus obtained melt through one or more nozzles;         and     -   e) cooling the melt till it solidifies.

The terms “melt” and “melting” should be interpreted broadly. These terms not only mean the alteration from a solid state to a liquid state, but can also refer to a transition to a glassy state or a rubbery state, and in which it is possible for one component of the mixture to get embedded more or less homogeneously into the other. In particular cases, one component will melt and the other component(s) will dissolve in the melt thus forming a solution, which upon cooling may form a solid solution having advantageous dissolution properties.

After preparing the solid dispersions as described hereinabove, the obtained products can be optionally milled and sieved.

The solid dispersion product may be milled or ground to particles having a particle size of less than 600 μm, preferably less than 400 μm and most preferably less than 125 μm.

The particles prepared as described hereinabove can then be formulated by conventional techniques into pharmaceutical dosage forms such as tablets and capsules.

It will be appreciated that a person of skill in the art will be able to optimize the parameters of the solid dispersion preparation techniques described above, such as the most appropriate solvent, the working temperature, the kind of apparatus being used, the rate of spray-drying, the throughput rate in the melt-extruder.

The water-soluble polymers in the particles are polymers that have an apparent viscosity, when dissolved at 20° C. in an aqueous solution at 2% (w/v), of 1 to 5000 mPa.s more preferably of 1 to 700 mPa.s, and most preferred of 1 to 100 mPa.s. For example, suitable water-soluble polymers include alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkyl alkylcelluloses, carboxyalkylcelluloses, alkali metal salts of carboxyalkylcelluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters, starches, pectines, chitin derivates, di-, oligo- and polysaccharides such as trehalose, alginic acid or alkali metal and ammonium salts thereof, carrageenans, galactomannans, tragacanth, agar-agar, gummi arabicum, guar gummi and xanthan gummi, polyacrylic acids and the salts thereof, polymethacrylic acids and the salts thereof, methacrylate copolymers, polyvinylalcohol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate, combinations of polyvinylalcohol and polyvinylpyrrolidone, polyalkylene oxides and copolymers of ethylene oxide and propylene oxide. Preferred water-soluble polymers are hydroxypropyl methylcelluloses.

Also one or more cyclodextrins can be used as water soluble polymer in the preparation of the above-mentioned particles as is disclosed in WO 97/18839. Said cyclodextrins include the pharmaceutically acceptable unsubstituted and substituted cyclodextrins known in the art, more particularly α-, β-, γ-cyclodextrins or the pharmaceutically acceptable derivatives thereof.

Substituted cyclodextrins which can be used to prepare the above described particles include polyethers described in U.S. Pat. No. 3,459,731. Further substituted cyclodextrins are ethers wherein the hydrogen of one or more cyclodextrin hydroxy groups is replaced by C₁₋₆alkyl, hydroxyC₁₋₆alkyl, carboxy-C₁₋₆alkyl or C₁₋₆alkyloxycarbonylC₁₋₆alkyl or mixed ethers thereof. In particular such substituted cyclodextrins are ethers wherein the hydrogen of one or more cyclodextrin hydroxy groups is replaced by C₁₋₃alkyl, hydroxyC₂₋₄alkyl or carboxyC₁₋₂alkyl or more in particular by methyl, ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxymethyl or carboxyethyl.

Of particular utility are the β-cyclodextrin ethers, e.g. dimethyl-β-cyclodextrin as described in Drugs of the Future, Vol. 9, No. 8, p. 577–578 by M. Nogradi (1984) and polyethers, e.g. hydroxypropyl β-cyclodextrin and hydroxyethyl β-cyclodextrin, being examples. Such an alkyl ether may be a methyl ether with a degree of substitution of about 0.125 to 3, e.g. about 0.3 to 2. Such a hydroxypropyl cyclodextrin may for example be formed from the reaction between β-cyclodextrin an propylene oxide and may have a MS value of about 0.125 to 10, e.g. about 0.3 to 3.

Another type of substituted cyclodextrins are sulfobutylcyclodextrines.

The ratio of the compound of formula (I) over the water soluble polymer may vary widely. For example ratios of 1/100 to 100/1 may be applied. Interesting ratios of the compound of formula (I) over cyclodextrin range from about 1/10 to 10/1. More interesting ratios range from about ⅕ to 5/1.

It may further be convenient to formulate the compounds of formula (I) in the form of nanoparticles which have a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than 1000 nm. Useful surface modifiers are believed to include those which physically adhere to the surface of the compound of formula (I) but do not chemically bond to said compound.

Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.

Yet another interesting way of formulating the compounds of formula (I) involves a pharmaceutical composition whereby the compounds of formula (I) are incorporated in hydrophilic polymers and applying this mixture as a coat film over many small beads, thus yielding a composition which can conveniently be manufactured and which is suitable for preparing pharmaceutical dosage forms for oral administration.

Said beads comprise a central, rounded or spherical core, a coating film of a hydrophilic polymer and a compound of formula (I) and optionally a seal-coating layer.

Materials suitable for use as cores in the beads are manifold, provided that said materials are pharmaceutically acceptable and have appropriate dimensions and firmness. Examples of such materials are polymers, inorganic substances, organic substances, and saccharides and derivatives thereof.

It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.

Those of skill in the treatment of HIV-infection could determine the effective daily amount from the test results presented here. In general it is contemplated that an effective daily amount would be from 0.01 mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.

The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore only guidelines and are not intended to limit the scope or use of the invention to any extent.

The present compounds of formula (I) can be used alone or in combination with other therapeutic agents, such as anti-virals, antibiotics, antifungals, immunomodulators or vaccines for the treatment of viral infections and opportunistic infections. They may also be used alone or in combination with other prophylactic agents for the prevention of viral infections. The present compounds may be used in vaccines and methods for protecting individuals against viral infections over an extended period of time. The present compounds may be employed in such vaccines either alone or together with other compounds of this invention or together with other anti-viral agents in a manner consistent with the conventional utilization of reverse transcriptase inhibitors in vaccines. Thus, the present compounds may be combined with pharmaceutically acceptable adjuvants conventionally employed in vaccines and administered in prophylactically effective amounts to protect individuals over an extended period of time against HIV infection.

Also, the combination of an antiretroviral compound and a compound of formula (I) can be used as a medicine. Thus, the present invention also relates to a product containing (a) a compound of formula (I), and (b) another antiretroviral compound, as a combined preparation for simultaneous, separate or sequential use in anti-HIV treatment. The different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers. Said other antiretroviral compounds may be known antiretroviral compounds such as suramine, pentamidine, thymopentin, castanospermine, dextran (dextran sulfate), foscarnet-sodium (trisodium phosphono formate); nucleoside reverse transcriptase inhibitors, e.g. zidovudine (3′-azido-3′-deoxythymidine, AZT), didanosine (2′,3′-dideoxyinosine; ddI), zalcitabine (dideoxycytidine, ddC) or lamivudine (2′-3′-dideoxy-3′-thiacytidine, 3TC), stavudine (2′,3′-didehydro-3′-deoxythymidine, d4T), abacavir and the like; non-nucleoside reverse transciptase inhibitors such as nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido-[3,2-b:2′,3′-e][1,4]diazepin-6-one), efavirenz, delavirdine, TMC-120, TMC-125 and the like; compounds of the TIBO (tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepine-2(1H)-one and thione)-type e.g. (S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo-[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione; compounds of the α-APA (α-anilino phenyl acetamide) type e.g. α-[(2-nitrophenyl)amino]-2,6-dichlorobenzene-acetamide and the like; inhibitors of trans-activating proteins, such as TAT-inhibitors, e.g. RO-5-3335, or REV inhibitors, and the like; protease inhibitors e.g. indinavir, ritonavir, saquinavir, lopinavir (ABT-378), nelfinavir, amprenavir, TMC-126, BMS-232632, VX-175 and the like; fusion inhibitors, e.g. T-20, T-1249 and the like; CXCR4 receptor antagonists, e.g. AMD-3100 and the like; inhibitors of the viral integrase; nucleotide-like reverse transcriptase inhibitors, e.g. tenofovir and the like; ribonucleotide reductase inhibitors, e.g. hydroxyurea and the like. By administering the compounds of the present invention with other anti-viral agents which target different events in the viral life cycle, the therapeutic effect of these compounds can be potentiated. Combination therapies as described above exert a synergistic effect in inhibiting HIV replication because each component of the combination acts on a different site of HIV replication. The use of such combinations may reduce the dosage of a given conventional anti-retroviral agent which would be required for a desired therapeutic or prophylactic effect as compared to when that agent is administered as a monotherapy. These combinations may reduce or eliminate the side effects of conventional single anti-retroviral therapy while not interfering with the anti-viral activity of the agents. These combinations reduce potential of resistance to single agent therapies, while minimizing any associated toxicity. These combinations may also increase the efficacy of the conventional agent without increasing the associated toxicity.

The compounds of the present invention may also be administered in combination with immunomodulating agents, e.g. levamisole, bropirimine, anti-human alpha interferon antibody, interferon alpha, interleukin 2, methionine enkephalin, diethyldithiocarbamate, tumor necrosis factor, naltrexone and the like; antibiotics, e.g. pentamidine isethiorate and the like; or cholinergic agents, e.g. tacrine, rivastigmine, donepezil, galantamine and the like to prevent or combat infection and diseases or symptoms of diseases associated with HIV infections, such as AIDS and ARC, e.g. dementia. A compound of formula (I) can also be combined with another compound of formula (I).

Although the present invention focuses on the use of the present compounds for preventing or treating HIV infections, the present compounds may also be used as inhibitory agents for other viruses which depend on similar reverse transcriptases for obligatory events in their life cycle.

Experimental Part

A. Preparation of the Intermediate Compounds

EXAMPLE A1

-   a. A solution of oxalyl bromide (8.82 g) in CH₂Cl₂ (50 ml) was added     dropwise to a suspension of 2-(methylamino)-propanenitrile     hydrobromide (3.30 g) in dichloromethane (200 ml). After addition, 3     drops of N,N-dimethylformamide were added and the resulting mixture     was immediately refluxed for 24 hours. After evaporation of the     solution, the residue was purified by column chromatography (silica     gel, 5% ethyl acetate in dichloromethane), yielding 3.90 g (69%) of     3,5-dibromo-1,6-dimethyl-2(1H)-pyrazinone (interm. 1; m.p. 119–120°     C.).     -   b. Methylaminoacetonitrile hydrochloride [CAS-25808-30-4] (43.91         g, 400 mmol) was treated with 150 ml of an aqueous solution of         K₂CO₃ (55.28 g, 400 mmol). This aqueous solution was extracted         with CH₂Cl₂ (4×150 ml). The dichloromethane solution was dried         over MgSO₄ and evaporated at 15–18° C. under reduced pressure.         The residue was dissolved in dry Et₂O and HBr gas was bubbled         through the solution. The precipitate was collected by         filtration and dried overnight in a dessicator, yielding 32.62 g         (54%) of methylaminoacetonitrile hydrobromide (interm. 2a). -   c. Preparation of intermediate 2

-    Oxalyl bromide (3.90 ml, 2.62 mmol) was added dropwise to a     suspension of intermediate 2a (2 g, 13.31 mmol) in CHCl₃ (50 ml),     followed by addition of tetraethylammonium bromide (1.45 g, 6.65     mmol). The reaction mixture was refluxed for 4 hours and then     evaporated. The residue was chromatographed on a silica gel column     (10% ethyl acetate in CH₂Cl₂), yielding 0.99 g (28%) of intermediate     2b ([MH+]=mass of the protonated compound determined by chemical     ionization mass spectrometry=267).

EXAMPLE A2

-   a. A mixture of intermediate 1 (1.50 g), 4-aminobenzonitrile (0.94     g), and camphorsulfonic acid (1.26 g) in 2-propanol (50 ml) was     refluxed (oil bath 120° C.) for 48 hours. After cooling of the     reaction mixture, the precipitate was collected by filtration and     successively washed with 2-propanol, aqueous potassium carbonate,     water and diethyl ether. Purification by column chromatography on     silica gel (5% ethyl acetate in CH₂Cl₂) afforded 1.42 g of     5-bromo-3-(4-cyanophenylamino)-1,6-dimethyl-2(1H)-pyrazinone     (interm. 3; m.p. 254–255° C.). -   b. Preparation of intermediate 4

-    A mixture of intermediate 2b (1.34 g; 5 mmol), 4-aminobenzonitrile     (0.904 g; 7.5 mmol), and 10-camphorsulfonic acid (1.18 g; 5 mmol) in     2-propanol (50 ml) was refluxed (oil bath 120° C.) for 48 hours.     After cooling of the reaction mixture, the precipitate was collected     by filtration and successively washed with 2-propanol, aqueous     potassium carbonate, water, and diethyl ether. Purification by     column chromatography on silica gel (10% ethyl acetate in CH₂Cl₂)     afforded 1.21 g (79%) of intermediate 4; m.p. 293–294° C.).

EXAMPLE A3

-   a. Preparation of intermediate 5

-    To a mixture of 19 g (100 mmol) of Na₂S₂O₃ and 8.81 g (200 mmol) of     acetaldehyde in 400 ml of water was added 21.4 g (200 mmol) of     benzylamine. After stirring for 4 hours at 60° C., the reaction     mixture was cooled to room temperature followed by addition of 13.03     g of KCN. This reaction mixture was stirred again at 60° C. for 15     hours. It was then extracted (2×250 ml) with CH₂Cl₂ and the organic     layer was washed with water, dried over MgSO₄, filtered and     evaporated. The resulting α-aminonitrile was dissolved in 300 ml of     diethyl ether. HCl gas was bubbled through the solution for 15     minutes at 0° C. The resulting α-aminonitrile hydrochloride was     filtered. The precipitate was washed with diethyl ether and dried     under vacuum, yielding 16.63 g (85%) of intermediate 5. -   b. Preparation of intermediate 6

-    Chlorobenzene (20 ml) was added at room temperature to intermediate     5 (16.63 g; 85 mmol) followed by dropwise addition of a solution of     oxalyl chloride (43 ml, 480 mmol) in 100 ml of chlorobenzene over 30     minutes, and 10 g of triethylammonium chloride. The reaction mixture     was stirred at room temperature for 2 days under nitrogen. After     evaporation of the solvent, the residue was purified by silica gel     column chromatography (using CH₂Cl₂ and 5% ethyl acetate in CH₂Cl₂     as eluent). Recrystallisation in EtOH afforded 14.41 g (63%) of     intermediate 6. -   c. Preparation of intermediate 7

-    A mixture of intermediate 6 (1.35 g; 5 mmol), 4-aminobenzonitrile     (0.904 g; 7.5 mmol), and 10-camphorsulfonic acid (1.18 g; 5 mmol) in     2-propanol (50 ml) was refluxed (oil bath 120° C.) for 48 hours.     After cooling of the reaction mixture, the precipitate was collected     by filtration and successively washed with 2-propanol, aqueous     potassium carbonate, water, and diethyl ether. Purification by     column chromatography on silica gel (5% ethyl acetate in CH₂Cl₂)     afforded 80% of intermediate 7 (m.p. 254° C.).

EXAMPLE A4

-   a. Preparation of intermediate 8

-    To a solution of dl-lactonitrile (2.243 g; 30 mmol) in toluene,     benzylamine (3.226 g; 30 mmol) was added. After stirring at room     temperature over night, the water formed was removed and the toluene     solution was dried over MgSO₄. After filtration and evaporation of     toluene, the resulting residue was dissolved in dry ethyl ether and     treated with hydrogen bromide at 0° C. for 30 minutes. The resulting     bromide salt was filtered and dried, yielding 6.87 g (95%) of     intermediate 8. -   b. Preparation of intermediate 9

-    A solution of oxalyl bromide (60 ml; 40 mmol) in CH₂Cl₂ (50 ml) was     added dropwise to a suspension of intermediate 8 (4.82 g; 20 mmol)     in CH₂Cl₂ (200 ml). After addition, a few drops (3) of     N,N-dimethylformamide were added and the resulting mixture was     immediately refluxed for 24 hours. After evaporation of the     solution, the residue was purified by column chromatography on     silica gel (5% ethyl acetate in CH₂Cl₂). After recrystallisation in     EtOH, 4.30 g (60%) of intermediate 9 was obtained (m.p. 126° C.). -   c. Preparation of intermediate 10

-    A mixture of intermediate 9 (1.79 g; 5 mmol), 4-aminobenzonitrile     (0.904 g; 7.5 mmol), and 10-camphorsulfonic acid (1.18 g; 5 mmol) in     2-propanol (50 ml) was refluxed (oil bath 120° C.) for 48 hours.     After cooling of the reaction mixture, the precipitate was collected     by filtration and successively washed with 2-propanol, aqueous     potassium carbonate, water, and diethyl ether. Purification by     column chromatography on silica gel (eluent: CH₂Cl₂) afforded 1.80 g     (91%) of intermediate 10 (m.p. 262° C.).     B. Preparation of the Final Compounds

EXAMPLE B1

-   a. Preparation of compound 26

-    A mixture of intermediate 3 (prepared according to A2.a) (0.32 g),     2,4,6-trimethylbenzenethiol (0.304 g), cesium carbonate (0.655 g),     copper (I) chloride (0.060 g) and 5 drops of ethyl acetate in     toluene (50 ml) was heated at 120° C. for 24 hours. After     evaporation of the solvent, the residue was purified by column     chromatography (silica gel, 40% hexane ii ethyl acetate). The     resulting product was repurified by column chromatography (1/1     mixture of hexane and ethyl acetate; 40% hexane in ethyl acetate),     yielding 129 mg of comp. 26. (m.p. 226–227° C.). -   b. Preparation of compound 20

-    A mixture of intermediate 3 (prepared according to A2a) (2.393 g;     7.5 mmol), 2,4-dimethylphenol (1.887 g; 15 mmol),     2,4,6-tri-tert-butylphenol (2.026 g; 7.5 mmol), cesium carbonate     (7.536 g; 23 mmol), copper (I) chloride (150 mg), and ethyl acetate     (1 ml) in toluene (500 ml) was heated at 120° C. for 24 hours. After     evaporation of the solvent, the residue was purified by column     chromatography (silica gel, 10% ethyl acetate in CH₂Cl₂) followed by     high performance liquid chromatography (40% hexanes in ethyl     acetate) to give 0.945 g (35%) of compound 20. -   c. Preparation of compound 1

-    A mixture of intermediate 3 (prepared according to A2.a) (0.24 g;     0.75 mmol), 4-hydroxy-3,5-dimethylbenzonitrile (0.22 g; 1.5 mmol),     cesium carbonate (0.344 g; 1.05 mmol), copper (I) chloride (0.04 g),     1-naphtoic acid (0.18 g; 1.05 mmol) and molecular sieves 4 Å     (0.20 g) was refluxed in toluene (30 ml) for 6 days. After     evaporation of the solvent, the residue was purified by column     chromatography (silica gel, 15% ethyl acetate in CH₂Cl₂) followed     high performance liquid chromatography (40% hexanes in ethyl     acetate) to give 28 mg of compound 1.

EXAMPLE B2

-    To a solution of compound 26 (0.101 g) in 15 ml CH₂Cl₂, was added     3-chloroperbenzoic acid (0.082 g). After 24 hours of stirring at     room temperature, the reaction mixture was washed with an aqueous     solution of potassium carbonate and dried before evaporation. Column     chromatography was performed on the residue eluting first compound     17 with 10% ethyl acetate in CH₂Cl₂ and then compound 18 with ethyl     acetate, yielding 0.033 g of compound 17 and 0.058 g of compound 18.

EXAMPLE B3

-   a. Preparation of compound 27

-    To a dry two-neck round flask under N₂ was added intermediate 7     (prepared according to A3.c) (2 mmol), dry 1-methyl-2-pyrrolidinone     (10 ml) and freshly thiocresol (0.523 g; 4 mmol). The solid Cs₂CO₃     (1.638 g; 5 mmol) was then added under N₂. The flask was then heated     in an oil bath at 130° C. for 3 hours while the contents of the     flask were stirred. After cooling to room temperature, the solvent     was evaporated under reduced pressure. Water was added to the     residue and extracted three times with CH₂Cl₂. The collected CH₂Cl₂     was washed with brine and dried over MgSO₄. After filtration and     removal of organic solvent, the crude products were purified by     column chromatography (silica gel, eluent 5% ethyl acetate in     CH₂Cl₂-10% ethyl acetate in CH₂Cl₂), yielding 0.525 g (60%) of     compound 27 (m.p. 195° C.). -   b. Preparation of compound 28

-    0.438 g (1 mmol) of compound 27 was added to dry o-dichlorobenzene     under N₂ followed by addition of 0.134 g (3 mmol) of AlCl₃. The     flask was then heated in an oil bath at 160° C. for 6 hours while     the contents of the flask were stirred. After cooling to room     temperature, the solvent was evaporated under reduced pressure. The     residue was washed with water and dried under vacuum.     Crystallisation by using ethyl acetate yielded 0.104 g (30%) of     compound 28 (m.p. 290–291° C.).

EXAMPLE B4

-    (0.381 g; 1 mmol), 2,4-dimethylphenol (0.252 g; 2 mmol), cesium     carbonate (0.819 g; 2.5 mmol), and catalytic amounts of copper (I)     chloride (50 mg) in toluene (60 ml) was heated at 110° C. for 48     hours. After cooling to room temperature, the solvent was evaporated     and the crude mixture was extracted with CH₂Cl₂ (three times). The     organic phase was dried over MgSO₄, filtered and evaporated. The     residue was purified by column chromatography (silica gel, 2–5%     ethyl acetate in CH₂Cl₂) followed by high performance liquid     chromatography (2% ethyl acetate in CH₂Cl₂), yielding 0.53 g (12.5%)     of compound 9 (m.p. 175° C.).

EXAMPLE B5

-    A mixture of intermediate 4 (prepared according to A2.b) (230 mg,     0.75 mmol), o-thiocresol (145 mg, 1.13 mmol), cesium carbonate (494     mg, 1.51 mmol) and copper (I) chloride (30 mg) in toluene (25 ml)     was heated at 120° C. for 36 hours. After cooling to room     temperature, the solvent was evaporated and the residue was     extracted with CH₂Cl₂. The organic phase was dried over MgSO₄,     filtered and evaporated. After column chromatography of the residue     on silica gel (5% ethyl acetate in CH₂Cl₂), two impure fractions     were obtained. The first fraction was further purified by     recrystallisation in ethyl acetate, yielding 0.071 g (20%) of     compound 5. The second fraction was further purified by high     performance liquid chromatography on silica gel (hexanes/ethyl     acetate: 2/3), yielding 0.078 g (30%) of compound 4.

Table 1 lists the compounds of formula (I) which were prepared according to one of the above examples.

TABLE 1

Comp No. Ex. No. R¹ R² R³ R^(4a) X Physical data 1 B1c CH₃ CH₃ 4-cyano-2,6- C≡N O 114–150° C. dimethyl-phenyl 2 B1a CH₃ H 2-methyl-phenyl C≡N O 202–204° C. 3 B1a CH₃ H 2,4-dimethyl- C≡N O 200.5–202° C.   phenyl 4 B5 CH₃ H 2-methyl-phenyl C≡N S 242.7–243.5° C. 5 B5 CH₃

2-methyl-phenyl C≡N S 266.8–267.4° C. 6 B1b CH₃ CH₃ 2-methyl-phenyl Cl O 222° C. 7 B1b CH₃ H 2,4-dimethyl- H O   166–166.5° C. phenyl 8 B1a CH₃ CH₃ 2,4-dimethyl- Cl S 213° C. phenyl 9 B4

H 2,4-dimethyl-phenyl C≡N O 175° C. 10 B4

H 2-methyl-phenyl C≡N O 199° C. 11 B1b CH₃ H 2,4-dimethyl- CF₃ O 147–148° C. phenyl 12 B1b CH₃ H 2,4-dimethyl- F O 151–152° C. phenyl 13 B1a CH₃ H 2,4,6-trimethyl- C≡N S 273–275° C. phenyl 14 B1a CH₃ H 2,4,6-trimethyl- Cl S 224–225° C. phenyl 15 B2 CH₃ H 2,4,6-trimethyl- C≡N S(═O)₂ 313–314° C. phenyl 16 B2 CH₃ CH₃ 2,4-dimethyl- C≡N S(═O)₂ 294–296° C. phenyl 17 B2 CH₃ CH₃ 2,4,6-trimethyl- C≡N S(═O)₂ 282–284° C. phenyl 18 B2 CH₃ CH₃ 2,4,6-trimethyl- C≡N S(═O) 239–240° C. phenyl 19 B1b CH₃ CH₃ 2-methyl-phenyl C≡N O 236° C. 20 B1b CH₃ CH₃ 2,4-dimethyl- C≡N O 208° C. phenyl 21 B1a CH₃ H 2,4-dimethyl- C≡N S 231–232° C. phenyl 22 B1a CH₃ H 2,4-dimethyl- Cl O 180–181° C. phenyl 23 B1b CH₃ CH₃ 2,4-dimethyl- Cl O 214° C. phenyl 24 B1a CH₃ CH₃ 2-methyl-phenyl C≡N S 240° C. 25 B1b CH₃ CH₃ 2,4,6-trimethyl- Cl O [MH+] = 374* phenyl 26 B1a CH₃ CH₃ 2,4,6-trimethyl- C≡N S 226–227° C. phenyl 27 B3a

CH₃ 2-methyl-phenyl C≡N S 195° C. 28 B3b H CH₃ 2-methyl-phenyl C≡N S 290–291° C. 29 B1b

CH₃ 2,4-dimethyl-phenyl C≡N O 147–149° C. 30 B1b CH₃ CH₃ 2,4,6-trimethyl- CF₃ O [MH+] = 418* phenyl *[MH+] is the mass of the protonated compound C. Pharmacological Example

The pharmacological activity of the present compounds was examined using the following test.

A rapid, sensitive and automated assay procedure was used for the in vitro evaluation of anti-HIV agents. An HIV-1 transformed T4-cell line, MT-4, which was previously shown (Koyanagi et al., Int. J. Cancer, 36, 445–451, 1985) to be highly susceptible to and permissive for HIV infection, served as the target cell line. Inhibition of the HIV-induced cytopathic effect was used as the end point. The viability of both HIV- and mock-infected cells was assessed spectrophotometrically via the in situ reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The 50% cytotoxic concentration (CC₅₀ in μM) was defined as the concentration of compound that reduced the absorbance of the mock-infected control sample by 50%. The percent protection achieved by the compound in HIV-infected cells was calculated by the following formula:

$\begin{matrix} \frac{\left( {OD}_{T} \right)_{HIV} - \left( {OD}_{C} \right)_{HIV}}{\left( {OD}_{C} \right)_{MOCK} - \left( {OD}_{C} \right)_{HIV}} & \; & {{{expressed}\mspace{14mu}{in}\mspace{14mu}\%},} \end{matrix}$ whereby (OD_(T))_(HIV) is the optical density measured with a given concentration of the test compound in HIV-infected cells; (OD_(C))_(HIV) is the optical density measured for the control untreated HIV-infected cells; (OD_(C))_(MOCK) is the optical density measured for the control untreated mock-infected cells; all optical density values were determined at 540 nm. The dose achieving 50% protection according to the above formula was defined as the 50% inhibitory concentration (IC₅₀ in μM). The ratio of CC₅₀ to IC₅₀ was defined as the selectivity index (SI). The compounds of formula (I) were shown to inhibit HIV-1 effectively. Particular IC₅₀, CC₅₀ and SI values are listed in Table 2 hereinbelow.

TABLE 2 Co. IC₅₀ CC₅₀ No. (μM) (μM) SI 1 0.0063 99.8 15849 2 0.0040 100.5 25119 3 0.0006 95.1 158489 4 0.02 100.2 5012 6 0.100 100 1000 7 0.1995 99.9 501 8 0.501 100.2 200 9 0.0316 99.9 3162 10 0.316 99.9 316 11 0.501 100.2 200 13 0.0158 99.7 6310 14 0.0794 99.9 1259 15 0.0079 99.4 12589 16 0.0316 99.9 3162 17 0.0050 99.8 19953 18 0.0040 100.5 25119 19 0.0050 99.8 19953 20 0.0025 99.5 39811 21 0.0050 99.8 19953 22 0.020 100.24 5012 23 0.0501 99.9 1995 24 0.0251 99.9 3981 

1. A compound of formula

a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof, wherein R¹ is hydrogen, hydroxy, cyano, amino, mono- or di(C₁₋₄alkyl)amino, formyl, carboxyl, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, polyhaloC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, aminocarbonyl, —S(═O)_(m)—NH₂, mono- or di(C₁₋₄alkyl)aminocarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy, aryl, arylC₁₋₆alkyl or aryloxy; R² is hydrogen; halo; mercapto; formyl; cyano; carboxyl; azido; hydroxy; oxiranyl; amino; mono- or di(C₁₋₄alkyl)amino; formylamino; R⁵R⁶N—C(═O)—; R⁷—N═C(R⁸)—; C₁₋₆alkyl-S(═O)_(m); aryl-S(═O)_(m); C₂₋₆alkenyl optionally substituted with one or two substituents each independently selected from halo, hydroxy, cyano, formyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy, N-hydroxy-imino, aryl or Het¹; C₂₋₆alkynyl optionally substituted with one or two substituents each independently selected from halo, hydroxy, cyano, formyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy, N-hydroxy-imino, aryl or Het¹; C₁₋₆alkyloxy; hydroxyC₁₋₆alkyloxy; aminoC₁₋₆alkyloxy; mono- or di(C₁₋₄alkyl)amino-C₁₋₆alkyloxy; C₁₋₆alkylcarbonyl; arylcarbonyl; Het¹carbonyl; C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyloxy; aryl; aryloxy; arylC₁₋₆alkyloxy; arylthio; arylC₁₋₆alkylthio; mono- or di(aryl)amino; Het¹; Het¹oxy; Het¹thio; Het¹C₁₋₆alkyloxy; Het¹C₁₋₆alkylthio; mono- or di(Het¹)amino; C₃₋₇cycloalkyl; C₃₋₇cycloalkyloxy; C₃₋₇cycloalkylthio; C₁₋₆alkylthio; hydroxyC₁₋₆alkylthio; aminoC₁₋₆alkylthio; mono- or di(C₁₋₄alkyl)aminoC₁₋₆alkylthio; C₁₋₆alkyl optionally substituted with one, two or three substituents each independently selected from halo, hydroxy, cyano, C₁₋₆alkyloxy, C₁₋₆alkylthio, hydroxy-C₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkylcarbonyl-oxy, aminocarbonyloxy, mono- or di(C₁₋₄alkyl)aminocarbonyloxy, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxycarbonyl-C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonylC₁₋₆alkylthio, aryl, Het¹, aryloxy, arylthio, arylC₁₋₆alkyloxy, arylC₁₋₆alkylthio, Het¹C₁₋₆alkyloxy, Het¹C₁₋₆alkylthio, C₁₋₆alkyl-S(═O)_(m)-oxy, amino, mono- or di(C₁₋₆alkyl)amino, formylamino, C₁₋₆alkyloxycarbonylamino, C₁₋₆alkyloxyC₁₋₆alkylcarbonylamino, mono- or di(aryl)amino, mono- or di(arylC₁₋₄alkyl)amino, (C₁₋₆alkyl)(arylC₁₋₄alkyl)amino, mono- or di(C₁₋₄alkyloxyC₁₋₄alkyl)amino, mono- or di(arylC₁₋₄alkyloxyC₁₋₄alkyl)amino, mono- or di(C₁₋₄alkylthioC₁₋₄alkyl)amino, mono- or di(arylC₁₋₄alkylthioC₁₋₄alkyl)amino, mono- or di(Het¹C₁₋₄alkyl)amino, mono- or di(C₁₋₄alkyl)aminoC₁₋₄alkyloxy, mono- or di(C₁₋₄alkyl)aminoC₁₋₄alkylthio, R⁹—C(═O)—NH—, R¹⁰—NH—C(═O)—NH—, R¹¹—S(═O)₂—NH—, or a radical of formula

 with A₁ representing CH or N, and A₂ representing CH₂, NR¹² or O, provided that when A₁ is CH then A₂ is other than CH₂, said radical of formula (a-1), (a-2) or (a-3) optionally being substituted with one or two substituents each independently selected from hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy, hydroxyC₁₋₄alkyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxycarbonyl-C₁₋₄alkyl, aminoC₁₋₆alkyl, carbonyl, hydroxy, cyano, amide, mono- or di(C₁₋₄alkyl)aminocarbonyl, mono- or di(C₁₋₄alkyl)aminoC₁₋₆alkyl, 4-hydroxy-phenyl, 4-cyano-phenyl; R³ and R⁴ each independently represent phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein each of said aromatic rings may optionally be substituted with one, two, three, four or five substituents each independently selected from hydroxy, halo, C₁₋₆alkyl optionally substituted with cyano or —C(═O)R¹³, C₃₋₇cycloalkyl, C₂₋₆alkenyl optionally substituted with one or more halogen atoms or cyano, C₂₋₆alkynyl optionally substituted with one or more halogen atoms or cyano, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano, aminocarbonyl, nitro, amino, mono- or di(C₁₋₆alkyl)amino, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, polyhaloC₁₋₆alkylthio, —S(═O)_(p)R¹³, —NH—S(═O)_(p)R¹³, —C(═O)R¹³, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R¹³,—C(═NH)R¹³ or a radical of formula

wherein each A independently is N, CH or CR¹³; B is NH, O, S or NR¹³; p is 1 or 2; and —X— is a bivalent radical selected from —NR¹⁴—; —NH—NH—; —N═N—; —O—; —C₁₋₆alkanediyl- which may optionally be substituted with halo, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy, mono- or di(C₁₋₆alkyl)amino, mono- or di(C₁₋₆alkyl)aminocarbonyl; —C(═O)—; —CHOH—; —S—; —S(═O)_(m)—; each m independently is 1 or 2; R⁵ and R⁶ each independently represent hydrogen or C₁₋₄alkyl optionally substituted with cyano, C₁₋₄alkyloxy, C₁₋₄alkylthio, amino, mono- or di(C₁₋₄alkyl)amino or a radical of formula

 with A₃ and A₄ each independently representing CH₂, NR¹² or O; R⁷ is hydrogen, hydroxy, C₁₋₄alkyloxy, carboxyC₁₋₄alkyloxy, C₁₋₄alkyloxycarbonyl-C₁₋₄alkyloxy, C₂₋₄alkenyloxy, C₂₋₄alkynyloxy or arylC₁₋₄alkyloxy; R⁸ is hydrogen, carboxyl or C₁₋₄alkyl; R⁹ is hydrogen; C₁₋₄alkyl optionally substituted with cyano, C₁₋₄alkyloxy, C₁₋₄alkyl-S(═O)_(m)—, aryl or Het²; C₁₋₄alkyloxy; C₂₋₄alkenyl; arylC₂₋₄alkenyl; Het²C₂₋₄alkenyl; C₂₋₄alkynyl; Het²C₂₋₄alkynyl; arylC₂₋₄alkynyl; C₃₋₇cycloalkyl; aryl; naphthyl; or Het²; R¹⁰ is C₁₋₄alkyl, arylC₁₋₄alkyl, aryl, arylcarbonyl, C₁₋₄alkylcarbonyl, C₁₋₄alkyloxycarbonyl, or C₁₋₄alkyloxycarbonylC₁₋₄alkyl; R¹¹ is C₁₋₄alkyl optionally substituted with aryl or Het³, polyhaloC₁₋₄alkyl, or C₂₋₄alkenyl optionally substituted with aryl or Het³; R¹² is hydrogen, C₁₋₄alkyl or C₁₋₄alkylcarbonyl; R¹³ is C₁₋₆alkyl, amino, mono- or di(C₁₋₆alkyl)amino or polyhaloC₁₋₆alkyl; R¹⁴ is hydrogen; aryl; formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl; C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy; or C₁₋₆alkyloxyC₁₋₆alkylcarbonyl substituted with C₁₋₆alkyloxycarbonyl; aryl is phenyl optionally substituted with one, two, three, four or five substituents each independently selected from hydroxy, halo, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro, polyhaloC₁₋₆alkyl and polyhaloC₁₋₆alkyloxy; Het¹ represents a monocyclic or bicyclic heterocycle selected from pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, hexahydropyrimidinyl, piperazinyl, hexahydropyridazinyl, benzopyrrolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl, 2-oxo-1,2-dihydroquinolinyl, each of said monocyclic or bicyclic heterocycle may optionally be substituted with one, two or three substituents each independently selected from halo, hydroxy, C₁₋₄alkyl, C₁₋₄alkyloxy, C₁₋₄alkylcarbonyl or polyhaloC₁₋₄alkyl; Het² represents a monocyclic or bicyclic heterocycle selected from pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyrrolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, quinolinyl, 2-oxo-1,2-dihydro-quinolinyl, quinolinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, hexahydropyrimidinyl, piperazinyl, and hexahydropyridazinyl or a radical of formula

 with A₅ or A₆ each independently being selected from CH₂ or O; each of said monocyclic or bicyclic heterocycle may optionally be substituted with one, two or three substituents each independently selected from halo, hydroxy,C₁₋₄alkyl, C₁₋₄alkyloxy, C₁₋₄alkylcarbonyl, polyhaloC₁₋₄alkyl or aryl; Het³ represents a monocyclic heterocycle selected from pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, each of said heterocycle may optionally be substituted with one, two or three substituents each independently selected from halo, hydroxy, C₁₋₄alkyl, C₁₋₄alkyloxy, C₁₋₄alkylcarbonyl or polyhaloC₁₋₄alkyl.
 2. A compound as claimed in claim 1 wherein R¹ is hydrogen, C₁₋₆alkyl or arylC₁₋₆alkyl; R² is hydrogen, C₁₋₆alkyl or arylthio; R³ and R⁴ are aryl and X is O, S or S(═O)_(m).
 3. A compound as claimed in claim 1 or 2 wherein R¹ is C₁₋₃alkyl or arylC₁₋₆alkyl.
 4. A compound as claimed in claim 3, wherein R¹ is methyl.
 5. A compound as claimed in claim 1, wherein R² is methyl.
 6. A compound as claimed in claim 1, wherein R³ or R⁴ is phenyl substituted with one, two or three substituents selected from cyano, aminocarbonyl, C₁₋₆alkyl, halo, polyhaloC₁₋₆alkyl.
 7. A compound as claimed in claim 1, wherein R⁴ is phenyl substituted with one of cyano, aminocarbonyl, C₁₋₆alkyl, halo, and polyhalomethyl.
 8. A compound as claimed in claim 1 wherein the compound is one of: 4-[[3,4-dihydro-4-methyl-6-(2-methylphenoxy)-3-oxopyrazinyl]amino]-benzonitrile; 4-[[6-(2,4-dimethylphenoxy)-3,4-dihydro-4-methyl-3-oxopyrazinyl]amino]-benzonitrile; 4-[[3,4-dihydro-4-methyl-6-[(2-methylphenyl)thio]-3-oxopyrazinyl]amino]-benzonitrile; 3-[(4-chlorophenyl)amino]-1,6-dimethyl-5-(2-methylphenoxy)-2(1H)-pyrazinone; 5-(2,4-dimethylphenoxy)-1-methyl-3-(phenylamino)-2(1H)-pyrazinone; 3-[(4-chlorophenyl)amino]-5-[(2,4-dimethylphenyl)thio]-1,6-dimethyl-2(1H)-pyrazinone; 4-[[6-(2,4-dimethylphenoxy)-3,4-dihydro-3-oxo-4-(phenylmethyl)pyrazinyl]amino]-benzonitrile; 4-[[6-(2,4-dimethylphenoxy)-3,4-dihydro-3-oxo-4-(phenylmethyl)pyrazinyl]amino]-benzonitrile; 5-(2,4-dimethylphenoxy)-1-methyl-3-[[4-(trifluoromethyl)phenyl]amino]-2(1H)-pyrazinone; 5-(2,4-dimethylphenoxy)-1-methyl-3-[[4-(trifluoromethyl)phenyl]amino]-2(1H)-pyrazinone; 4-[[3,4-dihydro-4-methyl-3-oxo-6-[(2,4,6-trimethylphenyl)thio]pyrazinyl]amino]-benzonitrile; 3-[(4-chlorophenyl)amino]-1-methyl-5-[(2,4,6-trimethylphenyl)thio]-2(1H)-pyrazinone; 4-[[3,4-dihydro-4-methyl-3-oxo-6-[(2,4,6-trimethylphenyl)sulfonyl]pyrazinyl]amino]-benzonitrile; 4-[[6-[(2,4-dimethylphenyl)sulfonyl]-3,4-dihydro-4,5-dimethyl-3-oxopyrazinyl]amino]-benzonitrile; 4-[[3,4-dihydro-4,5-dimethyl-3-oxo-6-[(2,4,6-trimethylphenyl)sulfonyl]pyrazinyl]amino]-benzonitrile; 4-[[3,4-dihydro-4,5-dimethyl-3-oxo-6-[(2,4,6-trimethylphenyl)sulfonyl]pyrazinyl]amino]-benzonitrile; 4-[[3,4-dihydro-4,5-dimethyl-6-(2-methylphenoxy)-3-oxopyrazinyl]amino]-benzonitrile; 4-[[6-(2,4-dimethylphenoxy)-3,4-dihydro-4,5-dimethyl-3-oxopyrazinyl]amino]-benzonitrile; 4-[[6-[(2,4-dimethylphenyl)thio]-3,4-dihydro-4-methyl-3-oxopyrazinyl]amino]-benzonitrile; 3-[(4-chlorophenyl)amino]-5-(2,4-dimethylphenoxy)-1-methyl-2(1H)-pyrazinone; 3-[(4-chlorophenyl)amino]-5-(2,4-dimethylphenoxy)-1,6-dimethyl-2(1H)-pyrazinone; 4-[[3,4-dihydro-4,5-dimethyl-6-[(2-methylphenyl)thio]-3-oxopyrazinyl]amino]-benzonitrile; 3-[(4-chlorophenyl)amino]-5-(2,4-dimethylphenylthio)-1,6-dimethyl-2(1H)-pyrazinone; 4-[[6-[(4-cyanophenyl)amino]-4,5-dihydro-3,4-dimethyl-5-oxopyrazinyl]oxy]-3,5-dimethyl-benzonitrile; 4-[4,5-dimethyl-3-oxo-6-(2,4,6-trimethyl-phenylsulfanyl)-3,4-dihydro-pyrazin-2-ylamino]-benzonitrile; 4-[[6-[(2-methylphenyl)thio]-5-methyl-3,4-dihydro-3-oxo-4-(phenylmethyl)pyrazinyl]amino]-benzonitrile; 4-[[3,4-dihydro-5-methyl-6-[(2-methylphenyl)thio]-3-oxopyrazinyl]amino]-benzonitrile; 4-[[6-(2,4-dimethylphenoxy)-5-methyl-3,4-dihydro-3-oxo-4-(phenylmethyl)pyrazinyl]amino]-benzonitrile; 5-(2,4,6-trimethylphenoxy)-5-methyl-1-methyl-3-[[4-(trifluoromethyl)phenyl]amino]-2(1H)-pyrazinone; a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof.
 9. A compound as claimed in claim 8 wherein the compound is one of: 4-[[3,4-dihydro-4-methyl-6-(2-methylphenoxy)-3-oxopyrazinyl]amino]-benzonitrile; 4-[[6-(2,4-dimethylphenoxy)-3,4-dihydro-4-methyl-3-oxopyrazinyl]amino]-benzonitrile; 4-[[3,4-dihydro-4-methyl-6-[(2-methylphenyl)thio]-3-oxopyrazinyl]amino]-benzonitrile; 3-[(4-chlorophenyl)amino]-1,6-dimethyl-5-(2-methylphenoxy)-2(1H)-pyrazinone; 5-(2,4-dimethylphenoxy)-1-methyl-3-(phenylamino)-2(1H)-pyrazinone; 3-[(4-chlorophenyl)amino]-5-[(2,4-dimethylphenyl)thio]-1,6-dimethyl-2(1H)-pyrazinone; 4-[[6-(2,4-dimethylphenoxy)-3,4-dihydro-3-oxo-4-(phenylmethyl)pyrazinyl]amino]-benzonitrile, 4-[[6-(2,4-dimethylphenoxy)-3,4-dihydro-3-oxo-4-(phenylmethyl)pyrazinyl]amino]-benzonitrile; 5-(2,4-dimethylphenoxy)-1-methyl-3-[[4-(trifluoromethyl)phenyl]amino]-2(1H)-pyrazinone, 5-(2,4-dimethylphenoxy)-1-methyl-3-[[4-(trifluoromethyl)phenyl]amino]-2(1H)-pyrazinone, 4-[[3,4-dihydro-4-methyl-3-oxo-6-[(2,4,6-trimethylphenyl)thio]pyrazinyl]amino]-benzonitrile; 3-[(4-chlorophenyl)amino]-1-methyl-5-[(2,4,6-trimethylphenyl)thio]-2(1H)-pyrazinone, 4-[[3,4-dihydro-4-methyl-3-oxo-6-[(2,4,6-trimethylphenyl)sulfonyl]pyrazinyl]amino]-benzonitrile; 4-[[6-[(2,4-dimethylphenyl)sulfonyl]-3,4-dihydro-4,5-dimethyl-3-oxopyrazinyl]amino]-benzonitrile, 4-[[3,4-dihydro-4,5-dimethyl-3-oxo-6-[(2,4,6-trimethylphenyl)sulfonyl]pyrazinyl]amino]-benzonitrile; 4-[[3,4-dihydro-4,5-dimethyl-3-oxo-6-[(2,4,6-trimethylphenyl)sulfinyl]pyrazinyl]amino]-benzonitrile; 4-[[3,4-dihydro-4,5-dimethyl-6-(2-methylphenoxy)-3-oxopyrazinyl]amino]benzonitrile, 4-[[6-(2,4-dimethylphenoxy)-3,4-dihydro-4,5-dimethyl-3-oxopyrazinyl]amino]-benzonitrile 4-[[6-[(2,4-dimethylphenyl)thio]-3,4-dihydro-4-methyl-3-oxopyrazinyl]amino]-benzonitrile; 3-[(4-chlorophenyl)amino]-5-(2,4-dimethylphenoxy)-1-methyl-2(1H)-pyrazinone; 3-[(4-chlorophenyl)amino]-5-(2,4-dimethylphenoxy)-1,6-dimethyl-2(1H)-pyrazinone; 4-[[3,4-dihydro-4,5-dimethyl-6-[(2-methylphenyl)thio]-3-oxopyrazinyl]amino]-benzonitrile; 3-[(4-chlorophenyl)amino]-5-(2,4-dimethylphenylthio)-1,6-dimethyl-2(1H)-pyrazinone; 4-[[6-[(4-cyanophenyl)amino]-4,5-dihydro-3,4-dimethyl-5-oxopyrazinyl]oxy]-3,5-dimethyl-benzonitrile; 4-[4,5-dimethyl-3-oxo-6-(2,4,6-trimethyl-phenylsulfanyl)-3,4-dihydro-pyrazin-2-ylamino]-benzonitrile; a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof.
 10. A compound as claimed in claim 8, wherein the compound is one of: 4-[[3,4-dihydro-4,5-dimethyl-6-(2-methylphenoxy)-3-oxopyrazinyl]amino]-benzonitrile; 4-[[6-(2,4-dimethylphenoxy)-3,4-dihydro-4,5-dimethyl-3-oxopyrazinyl]amino]-benzonitrile; 4-[[6-[(2,4-dimethylphenyl)thio]-3,4-dihydro-4-methyl-3-oxopyrazinyl]amino]-benzonitrile; 4-[[6-[(4-cyanophenyl)amino]-4,5-dihydro-3,4-dimethyl-5-oxopyrazinyl]oxy]-3,5-dimethyl-benzonitrile; a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof.
 11. A method for the treatment of HIV (Human Immunodeficiency Virus) infection, comprising administering to a subject in need thereof a medicament that comprises a therapeutically effective amount of a compound as claimed in any one of claims 1–10.
 12. A method for the treatment of multi drug resistant HIV infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as claimed in claim
 1. 13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a compound as claimed in claim
 1. 14. A process for preparing a pharmaceutical composition, comprising intimately mixing a compound as claimed in claim 1 with a pharmaceutically acceptable carrier.
 15. A product comprising (a) a compound as claimed in claim 1, and (b) another antiretroviral compound.
 16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredients (a) a compound as claimed in any one of claims 1 to 10, and (b) another antiretroviral compound.
 17. A method for treating an HIV infection, comprising administering to a subject in need thereof a therapeutically effective amount of a product according to claim is, wherein said constituents (a) and (b) are administered simultaneously separately, or sequentially.
 18. A process for preparing a compound as claimed in claim 1, comprising reacting an intermediate of formula (II), wherein W₁ represents a suitable leaving group, with an intermediate of formula (III) in the presence of a suitable catalyst, a suitable base, and a suitable solvent,

with R¹, R², R³, R⁴ and X as defined in claim
 1. 19. A process according to claim 18, wherein said reacting is performed at a temperature of about 110° C. or greater.
 20. A process according to claim 18, further comprising converting compounds of formula (I) into each other.
 21. A process according to claim 18, further comprising converting compounds of formula (I), into a therapeutically active non-toxic acid addition salt by treatment with an acid.
 22. A process according to claim 21, further comprising converting the acid addition salt into a free base by treatment with alkali.
 23. A process according to claim 18, further comprising preparing a stereochemically isomeric form of said compound or a N-oxide form of said compound. 